CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids

Amber Dahlin, Joshua Denny, Dan M. Roden, Murray H. Brilliant, Christie Ingram, Terrie E. Kitchner, James G. Linneman, Christian M. Shaffer, Peter Weeke, Hua Xu, Michiaki Kubo, Mayumi Tamari, George L. Clemmer, John Ziniti, Michael J. McGeachie, Kelan G. Tantisira, Scott T. Weiss, Ann Chen Wu

Research output: Contribution to journalArticle

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Abstract

Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case–control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma-related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta-analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10 05 ). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03–1.11; joint P = 2.3 x 10-06). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.

Original languageEnglish
Pages (from-to)350-359
Number of pages10
JournalImmunity Inflammation and Disease
Volume3
Issue number4
DOIs
Publication statusPublished - 01-12-2015

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Adrenal Cortex Hormones
Asthma
Single Nucleotide Polymorphism
Genome-Wide Association Study
Genes
Hospital Emergency Service
Hospitalization
Nasal Lavage
Population
Precision Medicine
Meta-Analysis
Joints
Logistic Models
Regression Analysis
Phenotype
Messenger RNA
Research

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Dahlin, A., Denny, J., Roden, D. M., Brilliant, M. H., Ingram, C., Kitchner, T. E., ... Wu, A. C. (2015). CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids. Immunity Inflammation and Disease, 3(4), 350-359. https://doi.org/10.1002/iid3.73
Dahlin, Amber ; Denny, Joshua ; Roden, Dan M. ; Brilliant, Murray H. ; Ingram, Christie ; Kitchner, Terrie E. ; Linneman, James G. ; Shaffer, Christian M. ; Weeke, Peter ; Xu, Hua ; Kubo, Michiaki ; Tamari, Mayumi ; Clemmer, George L. ; Ziniti, John ; McGeachie, Michael J. ; Tantisira, Kelan G. ; Weiss, Scott T. ; Wu, Ann Chen. / CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids. In: Immunity Inflammation and Disease. 2015 ; Vol. 3, No. 4. pp. 350-359.
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abstract = "Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case–control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma-related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta-analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10 05 ). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95{\%} CI 1.03–1.11; joint P = 2.3 x 10-06). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.",
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Dahlin, A, Denny, J, Roden, DM, Brilliant, MH, Ingram, C, Kitchner, TE, Linneman, JG, Shaffer, CM, Weeke, P, Xu, H, Kubo, M, Tamari, M, Clemmer, GL, Ziniti, J, McGeachie, MJ, Tantisira, KG, Weiss, ST & Wu, AC 2015, 'CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids', Immunity Inflammation and Disease, vol. 3, no. 4, pp. 350-359. https://doi.org/10.1002/iid3.73

CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids. / Dahlin, Amber; Denny, Joshua; Roden, Dan M.; Brilliant, Murray H.; Ingram, Christie; Kitchner, Terrie E.; Linneman, James G.; Shaffer, Christian M.; Weeke, Peter; Xu, Hua; Kubo, Michiaki; Tamari, Mayumi; Clemmer, George L.; Ziniti, John; McGeachie, Michael J.; Tantisira, Kelan G.; Weiss, Scott T.; Wu, Ann Chen.

In: Immunity Inflammation and Disease, Vol. 3, No. 4, 01.12.2015, p. 350-359.

Research output: Contribution to journalArticle

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AU - Dahlin, Amber

AU - Denny, Joshua

AU - Roden, Dan M.

AU - Brilliant, Murray H.

AU - Ingram, Christie

AU - Kitchner, Terrie E.

AU - Linneman, James G.

AU - Shaffer, Christian M.

AU - Weeke, Peter

AU - Xu, Hua

AU - Kubo, Michiaki

AU - Tamari, Mayumi

AU - Clemmer, George L.

AU - Ziniti, John

AU - McGeachie, Michael J.

AU - Tantisira, Kelan G.

AU - Weiss, Scott T.

AU - Wu, Ann Chen

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N2 - Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case–control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma-related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta-analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10 05 ). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03–1.11; joint P = 2.3 x 10-06). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.

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